Inactivation of ERK1/2-CREB Pathway Is Implicated in MK801-induced Cognitive Impairment.

OBJECTIVE: Schizophrenia (SZ) is associated with cognitive impairment, and it is known that the activity of cAMP response element binding protein (CREB) decreases in the brain of SZ patients. The previous study conducted by the investigators revealed that the upregulation of CREB improves the MK801-related SZ cognitive deficit. The present study further investigates the mechanism on how CREB deficiency is associated with SZ-related cognitive impairment. METHODS: MK-801 was used to induce SZ in rats. Western blotting and immunofluorescence were performed to investigate CREB and the CREB-related pathway implicated in MK801 rats. The long-term potentiation and behavioral tests were performed to assess the synaptic plasticity and cognitive impairment, respectively. RESULTS: The phosphorylation of CREB at Ser133 decreased in the hippocampus of SZ rats. Interestingly, among the upstream kinases of CREB, merely ERK1/2 was downregulated, while CaMKII and PKA remained unchanged in the brain of MK801-related SZ rats. The inhibition of ERK1/2 by PD98059 reduced the phosphorylation of CREB-Ser133, and induced synaptic dysfunction in primary hippocampal neurons. Conversely, the activation of CREB attenuated the ERK1/2 inhibitor-induced synaptic and cognitive impairment. CONCLUSION: These present findings partially suggest that the deficiency of the ERK1/2-CREB pathway is involved in MK801-related SZ cognitive impairment. The activation of the ERK1/2-CREB pathway may be therapeutically useful for treating SZ cognitive deficits.

Long noncoding RNA ATB promotes the epithelial-mesenchymal transition by upregulating the miR-200c/Twist1 axe and predicts poor prognosis in breast cancer.

Recent studies indicate that the long noncoding RNA ATB (lncATB) can induce the epithelial-mesenchymal transition (EMT) in cancer cells, but the specific cellular targets of lncATB require further investigation. In the present study, the upregulation of lncATB in breast cancer cells was validated in a TGF-ß-induced EMT model. Gain- and loss-of-function studies demonstrated that lncATB enhanced cell migration, invasion and clonogenicity in vitro and in vivo. LncATB promoted the EMT by acting as a sponge for the miR-200 family and restoring Twist1 expression. Subsequently, the clinical significance of lncATB was investigated in a cohort of breast cancer patients (N = 131). Higher lncATB expression was correlated with increased nodal metastasis (P = 0.036) and advanced clinical stage (P = 0.011) as well as shorter disease-free survival (P = 0.043) and overall survival (P = 0.046). These findings define Twist1 as a major target of lncATB in the induction of the EMT and highlight lncATB as a biomarker in breast cancer patients.

High salt induced hypertension leads to cognitive defect.

Although increasing evidences suggest a relationship between hypertension and brain function for years, it is still unclear whether hypertension constitutes a risk factor for cognitive decline and its underlying mechanism. In the present study, an experimental animal model of hypertension simply by feeding rats with high salt diet was employed. We found that long-term high salt intake caused a marked increase of systolic blood pressure linked to a declined regional cerebral blood flow. Fear conditioning and morris water maze behavioral test revealed that high salt diet induced hippocampal dependent spatial reference memory deficits, while a decreased synaptogenesis without neuronal loss in hippocampus was observed in high salt treated rats. Furthermore, we found that high salt induced a decrease of intracellular calcium, which inactivated CaMK II and resulted in dephosphorylation of CREB at Ser133. These findings suggest a novel etiopathogenic mechanism of cognitive deficit induced by hypertension, which is initiated by high salt diet.

Breast reconstruction with single-pedicle TRAM flap in breast cancer patients with low midline abdominal scar.

Breast reconstruction with transverse rectus abdominis myocutaneous (TRAM) flap is challenging in patients with low midline abdominal scar. In this study, we aimed to investigate the clinical feasibility of immediate breast reconstruction using single-pedicle TRAM (SP-TRAM) flaps in patients with low midline abdominal scar. There were 4 strict selection criteria: 1) presence at least 3 perforators on the pedicle side; 2) perforators with regional average flow velocity of >20 cm/s; 3) upper edge of the abdominal scar at least 4 cm from the umbilicus; and 4) scar age >1 year. Eight breast cancer patients with low midline abdominal scar (scar group) and 20 without (control group) underwent immediate breast reconstruction with SP-TRAM flaps consisting of zone I and III and zone II tissues. Flap complications, donor-site complications, and cosmetic results were compared between the two groups. All flaps survived and both groups presented similar flap and donor site complications, including fat necrosis, seroma, hematoma, infection, delayed wound healing, and abdominal hernia, and patients in both groups had similar aesthetic results (p > 0.05). Thus, the study demonstrated that breast reconstruction using SP-TRAM flap was a safe approach in carefully selected patients with low midline abdominal scar.

[Different ratio of hormone effects on Fritillaria cirrhosa bulb induction].

OBJECTIVE: To study the effects of different hormone induced bulb of Fritillaria cirrhosa seedling leaves, in order to provide an effective way to expant Fritillaria cirrhosa source. METHODS: Fritillaria cirrhosa seedling leaves were used as explants, orthogonal test was carried out to study the medium consisting of 6-BA, NAA, 2, 4-D and KT, and proliferation induced by direct bulb. Induction rate and average number of bulb producing was treated as the assessment indices, and the content of alkaloid of bulb was determined. RESULTS: The best medium formula for Fritillaria cirrhosa tissue culture seedling was MS+6-BA 2.0 mg/L +NAA 1.0mg/L +KT 1.0mg/L, the bulb induction rate was 83.37% and the average number of bulb was 17.27. The alkaloid content of induced bulb was 0.389%, which was 1.64 times that of wild Fritillaria cirrhosa bulb. CONCLUSION: This study provides a simple and rapid mehod for the production of tissue culture of Fritillaria cirrhosa bulb. It is useful for reasonable development and utilization of Fritillaria cirrhosa resources, as well as improvement of the quality of medicinal materials.

A concise synthesis of N-substituted fagomine derivatives and the systematic exploration of their α-glycosidase inhibition.

A novel and concise scheme has been developed successfully for the syntheses of N-substituted fagomine derivatives. The transformation of lactone (2) to 1,5-diol (3) was carried on with high yield (93-95%). The cyclization of 4 to 5 is a high stereoselective reaction (de value > 98%). It is disclosed that bulky substituent at N atom of the piperidine decreases the inhibition activity except those substituents having the ability of solvation or forming disulfide bond with M444 at the active site of α-glycosidase, which enhance the interaction with enzyme. Compounds with S-configuration at C-3 show greater activity than those with R-configuration. The structure-activity relationship study is also supported by molecular docking analysis.

Bioluminescence imaging of DNA synthetic phase of cell cycle in living animals.

Bioluminescence reporter proteins have been widely used in the development of tools for monitoring biological events in living cells. Currently, some assays like flow cytometry analysis are available for studying DNA synthetic phase (S-phase) targeted anti-cancer drug activity in vitro; however, techniques for imaging of in vivo models remain limited. Cyclin A2 is known to promote S-phase entry in mammals. Its expression levels are low during G1-phase, but they increase at the onset of S-phase. Cyclin A2 is degraded during prometaphase by ubiquitin-dependent, proteasome-mediated proteolysis. In this study, we have developed a cyclin A2-luciferase (CYCA-Luc) fusion protein targeted for ubiquitin-proteasome dependent degradation, and have evaluated its utility in screening S-phase targeted anti-cancer drugs. Similar to endogenous cyclin A2, CYCA-Luc accumulates during S-phase and is degraded during G2/M-phase. Using Cdc20 siRNA we have demonstrated that Cdc20 can mediate CYCA-Luc degradation. Moreover, using noninvasive bioluminescent imaging, we demonstrated accumulation of CYCA-Luc in response to 10-hydroxycamptothecin (HCPT), an S-phase targeted anti-cancer drug, in human tumor cells in vivo and in vitro. Our results indicate that a CYCA-Luc fusion reporter system can be used to monitor S-phase of cell cycle, and evaluate pharmacological activity of anti-cancer drug HCPT in real time in vitro and in vivo, and is likely to provide an important tool for screening such drugs.

Formation of two (6,3) networks showing structural diversity, Borromean topology and conformational chirality in the same crystal.

Reaction of two tripodal ligands, 2,4,6-tris(4-((2-methyl-benzimidazol-1-yl)methyl)phenyl)-1,3,5-triazine (L1) and 1,3,5-tris(4-((2-methyl-benzimidazol-1-yl)methyl)phenyl)benzene (L2), with AgSbF6 led to formation of two types (6,3) networks in one single crystal, of which one is three-fold Borromean topologically entangled while the other is independent, showing the same chirality and sandwiched Borromean stacking.

[Effect of opening point method of ziwu liuzhu on myocardial ischemia in the patient of stroke].

OBJECTIVE: To observe effect of opening point method of ziwu liuzhu on myocardial ischemia in the patient of stroke. METHODS: Thirty cases of stroke with myocardial ischemia were treated with opening acupoint according to time of the combination of reinforcing mother point and reducing son point of the heart channel in nazi method of ziwu liuzhu, and 30 cases in the control group were treated with acupuncture at Guangming (GB 37). Changes of electrocardiogram before and after treatment were recorded. RESULTS: ST-T segment raised significantly 30 min after treatment with ziwu liuzhu needling method as compared with the control group (P < 0.05), the treatment group being better than the control group. CONCLUSION: Excessive and deficient changes of the qi and blood in the meridians and collaterals are correlated with time rhythm, and ziwu liuzhu needling method can increase clinical therapeutic effect.